Compulsive cocaine use, defined as continued cocaine use despite the devastating consequences, is a defining feature of cocaine addiction. Research has been focusing on understanding how chronic cocaine use may alter the brain processes involved in reward, reinforcement, motivation, habit learning, stress and how such alterations may contribute to compulsive cocaine use. Tremendous progresses have been made in identifying the molecular changes underlying such alterations and these changes critically contribute to enhanced cocaine use. Despite the achievement, the fact that no pharmacotherapies have been successfully developed to effectively control compulsive cocaine use indicates that the research needs to be broadened to look for other mechanisms critically involved in regulation of cocaine use. The fact that addicts continue cocaine use despite being fully aware of the dire consequences, which would deter normal people from engaging in any behavior that results in such consequences, suggests that there is impairment in the brain function critically involved in such deterrence. Thus, weakening the brain mechanism involved in negative consequence-induced inhibition of cocaine use is the fundamental mechanism underlying the compulsive aspect of cocaine addiction. Although enhanced rewarding, reinforcing, motivational effects, stress response or habit-like cocaine use may contribute to the decreased regulation by negative consequences of cocaine use, they do not mediate the compulsive aspect of cocaine use because they do not weaken the mechanism underlying negative consequence-mediated inhibition of such behavior. The goal of this application is to identify the neuropharmacological mechanisms underlying chronic cocaine use-induced weakening of negative consequence-induced inhibition of cocaine-seeking behavior. Thus, this study has the potential to make a breakthrough in understanding the brain mechanisms underlying the compulsive nature of cocaine addiction. Such knowledge likely leads to discovery of new drug targets for development of anti-cocaine addiction pharmacotherapies. To this end, three specific aims are proposed. Aim 1 will determine the behavioral mechanism critically contributing to compulsive cocaine-seeking behavior. In particular, we will focus on the punishment process that is critically involved in inhibition of cocaine-seeking behavior by negative consequences. Aim 2 will determine the neuropharmacological mechanisms critically contributing to compulsive cocaine-seeking behavior. Aim 3 will identify the neural circuit involved in punishment-induced inhibition of cocaine-seeking behavior and determine how chronic cocaine use impairs the function of the circuit to induce compulsive cocaine-seeking behavior. The information from this application will shift our view on regulation of cocaine use from the single perspective of positive regulation to a new, more sophisticated perspective of coordinated regulation by both positive and negative consequences. Such a novel perspective will no doubt stimulate research on the mechanisms compulsive use of other drugs of abuse or other compulsive behavior.